General approach to the synthesis of optically active 2-carboxy-4-[3'-(diethoxyphosphinyl)propyl]-5-alkylpip erazines (CPP analogues)

Article abstract of DOI:10.1016/S0957-4166(97)00157-2

General stereospecific syntheses of the opticailly active title compounds are described. The procedures presented are based on readily available starting materials, such as piperazine alcohols, and can be arranged for multigram quantities.

Full text of DOI:10.1016/S0957-4166(97)00157-2

Tetrahedron: Asymmetr). Vo]. 8, No. 10, pp. 1633-1639, 1997
(~) 1997 Elsevier Science Ltd All rights reserved.
Printed in Great Britain
) Pergamon
~
PII: S0957-4166(97)00157-2
0957-4166/97 $17.00 + 0.00
General approach to the synthesis of optically active 2-carboxy-4-[3'-
(diethoxyphosphinyl)propyl]-5-alkylpiperazines (CPP analogues)
Massimo Falorni,* Andrea Porcheddu and Giampaolo Giacomelli
Dipartimento di Chimica, Universith di Sassari, Via Vienna 2, 1-07100 Sassari, Italy
Abstract: General stereospecific syntheses of the optically active title compounds are
described. The procedures presented are based on readily available starting materials, such
as piperazine alcohols, and can be arranged for multigram quantities. @ 1997 Elsevier
Science Ltd
The pharmacological action of the excitatory amino acids (EAA), L-glutamate and L-aspartate,
is well documented. I In this context, 2-carboxy-4-(3-phosphonopropyl)piperazine (CPP) has been
identified as a potent and selective antagonist of the N-methyi-D-aspartate (NMDA) subtype of the
glutamate receptor.2 Recently we have published3 the first stereocontrolled synthesis of (R)-CPP
starting from o'clo-Sar-Ser; following our interest in the field of NMDA antagonists we have carried
out the preparation of 5-alkyl substituted CPP-analogues 1 and 2.
~..~.,/PO3H2
~ P O 3 H 2
(...-"-,.v~ PO3H2
H
H
H
1
2
(RpCPP
A reliable retrosynthetic analysis for 1 and 2 suggested a correlation between the diastereo-
merically defined precursor, 2-carboxy-5-alkyl-4-[3'-(diethoxyphosphinyl)propyl]-piperazine, and 2-
hydroxymethyl piperazine, that can be prepared by reduction of serine-containing diketopiperazine
(Scheme 1). The availability of enantiomers of both the amino acids should enable the preparation of
all the four possible stereoisomers.
F~,, ~~ ' ' I P O 3 E t 2
Ri' N~_ P O 3 E t 2
H
H
R,, N~ .,..0
Scheme 1.
For a synthesis that could be applied on a multigram scale and follows also the rule of atom economy,
the main problem is the differentiation of the two nitrogen atoms in the piperazine ring. The presence
of the hydroxy group in the piperazine alcohols suggested the use of N,O-acetals as a protection
and differentiation of the nitrogen atom in the 1-position of the heterocyclic ring. After this step,
the oxazolidine ring should be removed and the hydroxymethyl group oxidised after the preliminary
protection of the N(I) atom and the quaternization of the N(4) atom. The complete synthesis of 1 (R=i-
* Corresponding author. Email: fmax@ssmain.uniss.it
1633

1634
M. F A L O R N I et al.
Pr) and 2 (R=i-Bu) is presented here as a representative example. However, the procedures reported
can be applied to 5-alkyl-2-hydroxymethyl piperazines as gencral method.
After a first attempt to prepare the N,O-acetonide derivatives of the aminoalcohols 3a-b, we preferred
to employ PhCHO owing to the better stability of N,O-benzylidene acetal ring and to minimize the
formation of byproduct (Scheme 2). Thus, the treatment of 3a and 3b with freshly distilled PhCHO in
the presence of 5 .~ molecular sieves in benzene at reflux for 30 min afforded the oxazolidines 4a-b in
high yields after bulb to bulb distillation. Concerning the structures 4a-b, NOE experiments confirmed
the presence of the oxazolidine ring involving the N(I) atom, thus excluding the formation of a six
membered ring involving N(4) atom. As shown by the GLC and I H NMR analysis, the products 4a-b
are a mixture of two epimers at C(9) in 85/15 ratio for 4a and in 55/45 ratio for 4b. The alkylation at
N(4) atom was carried out using Br(CH2)3PO(OEt)2 in the presence of Na2CO3 in various solvents:
best results were obtained using refluxing MeOH. After 24 h, the alkylphosphonates 5a and 5b were
recovered in 65-78% yield after chromatographic purification. In the subsequent step, the N,O-acetal
ring was removed by acid hydrolysis with 10% aq HCI at room temperature overnight.
3-5
R
(4
•
,
;
i , , i , i
5 6 L j A
R,,r
%3
a
b
i-Pr
i-Bu
S
R
phL'
i
~
2 7
O8
1'1"
H
~
I
H
OH
~
9
OH
H
3a-b
4a-b
5a-b
Reagents and conditions: i) PhCHO, 5A molecular sieves, 1/2
h reflux ii) Br(CH2)3PO(OEt)2 ' Na2CO 3,
MeOH, 24 h reflux, iii) HC110%, 12 h rl
S c h e m e 2.
Treatment of 5a with (Boc)20 and Na2CO3 in presence of catalytic NH2OH in CH2CI2/H20
gave, in quantitative yield, the N-Boc derivative (2S,5S)-6a. When the same treatment was applied
to 2-hydroxymethyl piperazines, having the (2R,5S) configuration, the reactions afforded the N-Boc
derivatives in very low yields. Other methodologies for Boc-group introduction did not give satisfactory
results. The use of the ethoxycarbonyl group, less hindered than Boc-group, for protecting the N(1)
atom, allowed us to overcome this problem. Thus, the treatment of 2c with C1COOEt, in benzene at
0°C for 1 b, afforded the 6b compound in 59% yield (Scheme 3).
[
"
"
"
~ PO3 Et2
R,
4
[ " " " " " / PO3Et2
'
iv,v
s f "
,
~
,
6
R
x
(')
, r " 7 < ,
I
I
1'1"
"
I
a
i-Pr
Boc
S
R
H
OH
X
OH
b
i-Bu C O O E t
5a-b
6a-b
Reagents and conditions: iv) Boc20, CH2CI2/H20, Na2CO3, NH2OH (cat), it, 8 h. v) CICOOI=t, benzene 0° C, lh
Scheme 3.
The ammonium salts 7a and 7b were obtained by adding MeI to the N(l)-protected aminoalcohols
6a and llb at r.t. in MeOH, for 24--48 h. Then the crude products were dissolved in water and washed
with CH2C12 affording the pure ammonium salts that were isolated in 83-94% yield respectively
(Scheme 4),

Optically active CPP analogues
1635
/ ' ~ " - . ~ PO3Et2
~
PO31Ft2
vii
~
PO3Et2
4
~
PO3Et2
i
R,,~ _N_
3
"
vi
~,
m
x •
I
X
I
OH
X
OH
X
O Q
H
OMe
6a-b
7a-b
8a-b
9a-b
6a-9a: R = i-Pr, X = Boc, (5S,2S); 6 b - 9 b : R = ~-6u, X = COOEt, (5S,2R)
Reagents and conditions: vi) Mel, MeOH, rt., 12 vii) NalO4, Acetone/H20, RuCI3 (cat), 0=C to ft.,
AcOH. ix) Xylene/MeCN, 140°C, 72 h. x) HCI(g), MeOH, 24 h.
h
1 h. viii)
Scheme 4.
The compounds 7a and 7b were then oxidised following the Sharpless procedure4 with sodium
periodate in the presence of catalytic amounts of RuCI3.5 The oxidation mixtures were filtered on
Celite pad, affording, after removal of inorganic salts, the crude acids 8a-b in 65-88% yield, as light
brown foams. The structures of acids 8a-b were confirmed by IH NMR analysis and by elementary
analysis. Attempts to carry out the demethylation of these crude acids using PhSNa6 were however
unsuccessful. Thus, demethylation was achieved by using the acetate anion as nucleophile: the crude
oxidation products were then lyophilised from acetic acid solutions affording the acetates. Heating at
140°C for 72 h of the acetates in xylene/acetonitrile as solvent afforded the corresponding demethylated
amino acids, which were recovered in satisfactory yields from the reaction mixture as methyl esters
9a and 9b, by treatment with HCI in MeOH at rt.7 Measurements of ]H and 13C NMR spectra
carried out at various temperatures (from 20° to 50°C) have indicated that both compounds 9a and
9b have a diastereoisomeric purity _>97%. Subsequent treatment with 6 N HCI (reflux, 12 h) restored
the phosphonic acid moiety and removed the N(1 ) protecting group. However, the recovery of 1 or 2
as free amino acids by using ion exchange chromatography gave poor results, the target compounds
being recovered only in small quantities. 8
Experimental section
Melting and boiling points are uncorrected. Bulb to bulb distillations were carried out with a
Btichi GRK-51 apparatus equipped with a vacuum controller B/ichi B-168. Elemental analyses were
performed on a Perkin-Elmer 420 B analyzer. Optical rotations were measured with a Perkin-Elmer
241 automatic polarimeter in a 1 dm tube. GC analyses of the reaction products were carried out on
a Perkin-Elmer 8600 gas-chromatograph on fused silica megabore columns (15 m × 0.53 mm) DB-
1, DB-5 (J&W), operating with a He flow rate of 9 mL/min. The IH NMR (300 MHz), ]3C NMR
(75.4 MHz) and 31p (121.4 MHz) Fourier transform spectra were obtained with a Varian VXR-300
spectrometer on CDCI3 solutions (unless otherwise specified). All reactions involving air sensitive
materials were carried out under argon atmosphere; all reagents and solvents employed were reagent
grade materials purified by standard methods and distilled before use. (2S,5S)-2-Hydroxymethyl-5-iso-
propylpiperazine, 3a, [(X]D25 +5.61 (c 1, CHCI3), and (2R,5S)-2-hydroxymethyl-5-iso-butylpiperazine,
3b, [(X]D25 +4.9 (c 9, CHCI3) were prepared as previously reported.9
General procedure for 4a and 4b
A solution of 5-alkyl-2-hydroxymethylpiperazine 3a and 3b (11.4 mmol) and freshly distilled
benzaldehyde (12.5 mmol) in dry benzene (40 mL) was placed in a 100 mL two-necked-flask and
heated at reflux in presence of activated molecular sieves (5 ,~), under N2 atmosphere. After 1 h the
mixture was concentrated at reduced pressure (20 mBar) and the crude product bulb to bulb distilled
(150°C) to give pure (GLC) protected piperazine 4a and 4b.

1636
M. FALORNI et al.
(3S,6S,9RS)-9-Phenyl-3-iso-propyl- l, 4-diaza-8-oxa[4.3.0. ]bio,clononane 4a
94%, colourless oil. IH NMR 5:85/15 mixture of two diastereoisomers, 7.48-7.41 (m, 2H, Ph),
7.39-7.24 (m, 3H, Ph), 5.51 (s, 0.15H, PhCH), 4.60 (s, 0.85H, PhCH), 4.24 (t like, 0.15H, NCHCH20),
4.05 (t like, 0.85H, NCHCH20), 3.66 (dd like, IH, NCHCH20), 3.22 (dd like, IH), 2.72 (t like,
1H), 2.68 (dd like, 1H), 2.63-2.52 (m, IH), 2.50--2.43 (m. IH), 1.88 (t like, 1H), 1.60-1.46 [m, 1H,
CH(CH3)2] 1.40 (bs, 1H, NH), 0.95 [d, 3H, J=6, CH(CH3)2], 0.85 ppm [d, 3H, J=6, CH(CH3)2].
13C NMR 8: 138.7, 129.0, 128.2, 127.4, 96.3, 69.4, 68.6, 62.3, 60.1,56.7, 56.4, 50.7, 48.0, 47.4, 31.4,
19.1 ppm. Calculated for CI5H22N20: C, 73.13; H, 9.0; N, 11.37. Found: C, 73.0; H, 8.93; N, 11.41.
(3S, 6R, 9RS)- 9-Phenyl-3-iso-buO, l- 1,4-diaza-8-oxa[4.3. O. ]bicyclononane 4b
72%, colourless oil. IH NMR 8:55/45 mixture of two diastereoisomers, 7.50-7.41 (m, 2H, Ph),
7.39-7.29 (m, 3H, Ph), 5.57 (s, 0.55H, PhCH), 5.20 (s, 0.45H, PhCH), 3.98-3.79 (m, 2H, NCHCH20),
3.25-3.15 (m, IH), 3.10-2.91 (m, 2H), 2.91-2.82 (m, 1H), 2.50 (t like, IH), 2.22-2.10 (m, IH), 1.80
(bs, IH, NH), 1.75-1.65 [m, 1H, CH2CH(CH3)2], 1.42-1.11 [m, 2H, CH2CH(CH3)2], 0.92 [d, 3H,
J=6, CH2CH(CH3)2], 0.83 ppm [d, 3H, J=6, CH2CH(CH3)2]. 13C NMR 8: 136.8, 128.5, 127.6,
126.0, 99.0, 96.4, 90.2, 65.8, 63.8, 60.2, 55.6, 54.0, 51.0, 49.6, 43.7, 42.0, 24.5, 24.3, 23.2, 22.5, 22.2
ppm. Calculated for C16H24N20: C, 73.81; H, 9.29; N, 10.76. Found: C, 73.90; H, 9.11; N, 10.37.
General procedure for 5a and 5b
Protected piperazines 4a and 4b (6.1 mmol) were dissolved in absolute methanol (50 mL) and sodium
carbonate (9.4 mmol) and diethyl (bromopropyl)phosphonate (12.5 mmol) were added. The reaction
was refluxed for 24 h under N2 atmosphere. After filtration, the methanol solution was concentrated
under reduced pressure. The brown oil residue was placed on a silica gel column and eluted with
AcOEt/CH2CI2/MeOH 7/1/2. The crude compound was dissolved in 10% aq HCI (30 mL) and stirred
at r.t. for 12 h. Then, the aqueous solution was made alkaline with KOH and extracted with CH2C12
several times. The collected organic phases were dried (Na2SO4) and the solvent eliminated under
vacuum affording pure (TLC: AcOEt/CH2CI2 7/3) N-alkylated piperazine methanols 5a and 5b.
(2S~5S)~2-Hydr~.methy~4-[3~-(dieth~x~.~ph~sphinyl)pr~pyl]-5-is~-pr~pylpiperazine 5a
65%; [0t]D25 +21.8 (c 0.6, CHCI3); IH NMR 8:4.19-4.00 [m, 4H, P(OCH2CH3)2], 3.85 (dd, 1H,
Jl=l 1, J 2=3, CH2OH), 3.41 (dd, IH, J 1=11, J 2=5, CH2OH), 2.95-2.66 (m, 4H), 2.38-2.25 (m,
2H), 2.24-2.12 (m, 2H), 2.10-1.99 (m, IH), 1.98-1.88 (m, IH), 1.80-1.62 (m, 5H), 1.25 [t, 6H, J=7,
P(OCH2CH3)2], 0.86 [d, 3H, J=7, CH(CH3)2], 7.76 ppm [d, 3H, J=7, CH(CH3)2]; 13C NMR 8:
64.1,61.3, 59.9, 54.9, 52.6, 50.3, 47.0, 26.3, 24.4, 22.5, 19.8, 19.1, 16.3 ppm; 31p NMR 8:32.9 ppm.
Calculated for C15H33N204P: C, 53.56; H, 9.89; N, 8.33. Found: C, 53.57; H, 9.85; N, 8.36.
(2R~5S )-2-Hydr~x)'methyl~4-[ 3~-(dieth~xyph~sphinyl)pr~pyl]-5-is~-pr~py~piperazine 5b
78%; [a]D25 +27.8 (c 2.5, CHCI3); 1H NMR 5:4.15-4.02 [m, 5H, P(OCH2CH3)2+CH2OH],
3.90-3.81 (dd like, 1H, CH2OH), 3.65-3.43 (m, 2H), 2.72-2.60 (m, 2H), 2.58-2.37 (m, 4H), 2.38-2.30
(m, 1H), 1.80-1.62 (m, 5H), 1.55-1.40 [m, 2H, CH2CH(CH3)2], 1.25-1.16 [m, 1H, CH(CH3)2], 1.28
[t, J=7, 6H, P(OCH2CH3)2], 0.89 [d, J=7, 3H, CH(CH3)2], 0.80 ppm [d, J=7, 3H, (CH3)2]; 13C NMR
8: 71.2, 65.9, 65.6, 59.7, 58.5, 57.5, 52.7, 52.2, 45.8, 25.5, 24.1, 22.8, 19.8, 16.6 ppm; 31p NMR 8:
34.1 ppm. Calculated for C16H35N204P: C, 54.84; H, 10.07; N, 7.99. Found: C, 54.8; H, 10.1; N, 8.03.
(2S, 5S)• •-(tert•But•©•carb•nyl)-2-hydr•xymethy•-4•[
perazine 6a
y-I dieth•xyph•sphinyl )pr•pyl]-5-is•-pr•pylpi-
A solution of compound 5a (1.0 g, 3.0 mmol) in CH2CI2 (15 mL), solid BoczO (0.65 g, 3.0
mmol), Na2CO3 (0.6 g, 5.7 mmol) and NH2OH. HC1 (10% mol) in H20 (15 mL) were mixed together
and stirred for 48 h at r.t. The organic and aqueous layers were separated and the aqueous layer
extracted with CH2C12 (20 mL). The combined organic phases were washed with H20, dried (Na2SO4)

Optically active CPP analogues
1637
then evaporated under reduced pressure. The crude product was purified by flash chromatography
(AcOEt/CH2CI2 2/8) to furnish the protected 6a (1.25 g, 97%) having: [~X]D25 -- 1.65 (c 3.25, CHCI3);
IH NMR 8:4.0-3.85 [m, 4H, P(OCH2CH3)2], 3.81 (dd, Jl=14, J2=8, 1H, CH2OH), 2.82 (dd, Jl=14,
J2=4, 1H, CH2OH), 2.65-2.55 (m, 3H), 2.42-2.35 (m, IH), 2.28-2.10 (m, 2H), 2.05-1.09 (mb, 3H),
!.65-1.40 (m, 5H), 1.34 [s, 9H, C(CH3)3], 1.19 [t, 6H, J=7, P(OCH2CH3)2], 0.78 [d, J=7, 3H,
CH(CH3)2], 0.72 ppm [d, J=7, 3H, CH(CH3)2]; 13C NMR 6: (mixture of two conformers) 155.4,
81.7, 66.7, 63.4, 61.1, 61.0, 58.1, 55.0, 53.9, 53.6, 52.0, 51.7, 50.5, 27.4, 25.9, 24.0, 23.9, 22.2, 22.1,
19.6, 18.3, 18.2, 17.9, 17.8, 16.2, 16.1. ppm. Calculated for C20H41N206P: C, 55.86; H, 9.92; N, 6.2.
Found: C, 55.93; H, 10.03; N, 6.31.
(2R~5S)./.Eth~xycarb~ny/.2.hydr~x3;methy/.[4.(3'.(dieth~xyph~sphiny/)pr~py~].5.is~.bu~/pipera.
zine 6b
To a solution of amino alcohol 5b (1 g, 2.8 mmol) and NEt3 (0.4 g, 3.9 mmol), in dry benzene,
CICOOEt (0.3 g, 2.8 mmol) was added at 0°C under N2. The mixture was stirred at 0°C for 1 h
then at r.t. for an additional hour. The white solid formed was filtered off and the resulting solution
washed with 10% aq. HCI (3× 10 mL). The aqueous solutions were made alkaline with solid KOH,
saturated with NaC1 and extracted with CH2C12 several times. The collected organic phases were
dried (Na2SO4) and the solvent was eliminated under vacuum affording the product 6b (0.7 g, 59%),
pure (TLC, AcOEt/MeOH 85/15) having: [CX]D25 +83.01 (c 3.95, CHCI3), IH NMR 8 4.15-3.98 (m,
8H), 3.88-3.80 (m, 2H), 3.08 (d like, 1H), 2.85-2.72 (m, 2H), 2.38-2.24 (m, IH), 2.23-2.08 (m, 2H),
1.85-1.53 (m, 5H), 1.50-1.37 (m, 1H) 1.30 [t, 7H, J=7, P(OCH2CH3)2+CH2CH(CH3)2], 1.23 (t, 3H,
J=7, COOCH2CH3), 1.12-1.01 [m, IH, CH(CH3)2], 0.89 [d, 3H, CH(CH3)2] 0.86 ppm [d, 3H, J=7,
CH(CH3)2]; 13C NMR 8: 155.8, 64.4, 63.7, 61.4, 61.3, 58.2, 56.2, 52.7, 52.3, 51.5, 46.0, 40.2, 25.0,
23.8, 21.8 19.1 16.4 ppm. Calculated for CI9H39N206P: C, 54.0; H, 9.31; N, 6.63. Found: C, 53.90;
H, 9.40; N, 6.60.
(2S~5S)~-(tert-But~x3~carb~nyl)-2-hydr~.~methyl-4-[ y-(dieth~ph~sphinyl)pr~pyl]-4-methy~-5-is~-
propyl piperazinium iodide 7a
Methyl iodide (2 mL, 21 mmol) was added to the protected derivates 6a ( 1.0 g, 2.3 mmol) in MeOH
(20 mL). After 18 h under stirring, all the volatile products were eliminated under reduced pressure
and the residues partitioned between CH2C12 and H20. The organic layers were discarded and the
aqueous phases concentrated under vacuum affording pure (TLC) ammonium salt 7a: (1.1 g, 83%),
[a]D z5 +65.3 (c 1.35, CH3COOH); IH NMR (D20) 6:4.13-4.00 [m, 6H, P(OCH2CH3)2+CH2OH],
3.82 (dd like, 2H), 3.22 (s, 1.2H, N-Me), 2.90 (s, 1.8H, N-Me), 2.90-2.70 (m, 2H), 2.60-2.40 (m,
IH), 2.30-2.10 (m, IH), 1.88-1.60 (m, 4H), 1.35 (m, 3H), 1.26 [s, 9H, C(CH3)3], 1.11 [t, 6H, J=7,
P(OCH2CH3)2], 0.89 [d, J=7, 3H, CH(CH3)2], 0.75 ppm [d, J=7, 3H, CH(CH3)2]; 13C NMR (D20)
8: 146.8, 79.3, 67.6, 61.5, 61.4, 61.1, 59.8, 58.0, 56.2, 46.2, 46.0, 25.0, 23.8, 19.1, 18.9, 16.4, 16.0,
17.2, 16.3 ppm. Calculated for C21H44N206PI: C, 43.60: H, 7.67; N, 4.84. Found: C, 43.3; H, 7.65;
N, 4.88.
(2R'5S)- ~-Eth~xycarb~ny~-2-hydroxymethyl-4-[ y-( dieth~xyph~sphinyl)pr~py~]-4-methy~- 5-is~-bu~'l
piperazinium iodide 7b
Methyl iodide (4 mL, 42 retool) was added to the protected derivates 6h (0.65 g, 1.5 mmol) in
MeOH (20 mL). After 48 h the reaction was worked up as previously described for 7a to afford
pure (TLC) ammonium salt 7b: (0.8 g, 94%), [oc]o25 +52.4 (c 2.5, CH3COOH); I H NMR (D20)
8:4.11-3.94 [m, 8H, P(OCHzCH3)z+OCHzCH3+CH2OH], 3.86-3.60 (m, 3H), 3.55-3.38 (m, 3H),
3.35-3.20 (m, 2H), 3.06 (s, 1.3H, N-Me), 2.95 (s, 1.7H, N-Me), 2.05-1.75 (m, 3H), 1.70-1.58 (m,
2H), 1.49-1.32 (m, 2H), 1.19 [t, 6H, J=7, P(OCHzCH3)2], 1.12 (t, 3H, J=7, OCH2CH3) 0.87 [d, 3H,
J=7, CH(CH3)2], 0.84 ppm [d, 3H, J=7, CH(CH3)2]; 13C NMR (D20) 8: 152.0, 77.3, 68.6, 68.0,
59.7, 59.4, 49.2, 48.4, 48.1, 42.7, 34.2, 34.1, 31.7, 29.3, 29.1, 24.7, 24.6, 24.5 ppm. Calculated for
C2oH42N206PI: C, 42.56; H, 7.5; N, 4.96. Found: C, 42.48; H, 7.41; N, 5.01.

1638
M. FALORNI et al.
(2S~5S)- ~(tert~But~xycarb~ny~)~2~carb~`4.[3~-(dieth~xv~h~sphinyl)~r~pyl].4.methyl~5.is~-Pr~yl
piperazinium 8a
Under stirring at 0°C, NaIO4 (3.5 g, 11 retool) in water (40 mL) and RuCI3 hydrate (0.08 g) were
added to ammonium salt 7a (1 g, 1.7 retool) in acetone (60 mL). The reaction mixture was stirred for
1 h at 0°C and for an additional hour at r.t., then quenched with iso-propanol (4 mL). After 2 h, the
reaction mixture was filtered through a Celite pad and the filtrate concentrated under vacuum. The
residue was dissolved in H20 (10 mL) and washed with CC14 (2x20 mL) and CH2C12 (2×25 mL),
then the organic phase was discarded and the aqueous solution evaporated to give 8a (0.65 g, 82%),
[~]D 25 +43.21 (c 1.35, CH3COOH); IH NMR (D20) c5:4.1-3.9 [m, 4H, P(OCH2CH3)2], 3.3-3.5
(m, 3H), 2.3-2.4 (m, 3H), 2.1 (s, 1.6H, N-CH3), 2.3-2.1 (m, 3H), 1.8 (s, 1.4H, N-CH3), 1.6-1.4 (m,
3H), 1.33 [s, 9H, C(CH3)3], 1.12-1.15 [t, J=7, 6H, PO(CH2CH3)2], 0.84 [d, J=7, 3H, CH(CH3)2],
0.80 ppm [d, J=7, 3H, CH(CH3)2]; 13C NMR (D20) 8:185.9 148.6, 75.8, 72.1,63.0, 55.3, 49.2, 41.5,
37.9, 36.7, 32.1, 30.3, 28.3, 28.5, 25.6, 25.4, 24.1, 22.6, 21.5 ppm; Calculated for C21H41N207P: C,
54.3; H, 8.9; N, 6.03. Found: C, 54.22; H, 9.01 N, 6.1.
(2R,5S)- ~( Eth~xycarb~nyl)-2~carb~x3~-4~[ y-(dieth~x3.ph~sphinyl)pr~yl]~methyl~5~is~bu~ pipe-
razinium 8b
Under stirring at 0°C, NalO4 (4.6 g, 11 mmol) in water (40 mL) and RuC13 hydrate (0.08 g) were
added to ammonium salt 7b (1.2 g, 2.2 mmol) in acetone (60 mL). The reaction was worked up as
previously des,-ribed for 8a to afford to gi ce 8b (0.60 g, 59%" [~]D25 +24.1 (C 1.27, CH3COOH);
1H NMR (D20) 5:4.12-3.91 [m, 8H, P(OCH2CH3)2+OCH2CH3+CH20H], 3.50-3.34 (m, 2H),
3.30-3.13 (m, 2H), 3.08-2.99 (m, IH), 2.98 (s, 1.5H, N-CH3), 2.75 (s, 1.5H, N-CH3), 2.06-1.73
(m, 4H), 1.64-1.43 (m, 2H), 1.42-1.24 (m, 1 H), 1.17 It, J=7, 6H, PO(CH2CH3)2], 1.05 (t, J=7, 3H,
OCH2CH3), 0.83 [d, J=7, 3H, CH(CH3)2], 0.80 ppm [d, J=7, 3H, CH(CH3)2]; 13C NMR (D20) •:
165.2, 151.9, 80.7, 68.4, 66.9, 61.2, 60.2, 58.5, 49.2, 48.3, 42.0, 33.8, 31.2, 30.0, 28.5, 24.3, 23.6, 22.2
ppm; Calculated for C20H39N207P: C, 53.3; H, 8.73; N, 6.22. Found: C, 53.28; H, 8.80; N, 6.31.
(2S~5S )-2-Carb~xvmethyl-4-[ y-( dieth~x3~ph~sphinyl)pr~py~ ]-5-is~-pr~pylpiperazine 9a
The crude acid 8a (0.34 g, 0.8 mmol) was treated with glacial acetic acid (0.05 g, 0.82 mmol).
After 3 h the acetic solution were lyophilised affording pure (TLC) protected acetate (0.38 g, 0.78
mmol).The acetate (0.05 g, 0.78 mmol) was suspended in xylene/acetonitrile (85/15, 100 mL) and
heated, under stirring, at 140°C. After 26 h, the reaction mixture was evaporated under vacuum and
the residue treated with H20 and extracted with Et20 (2x 10 mL). The organic phase was discarded
and the aqueous layers recovered and evaporated under vacuum. The residue was dissolved in dry
MeOH and gaseous HCI was added after 24 h at room temperature: the reaction mixture was reduced
to half of the volume and treated with ion exchange resin (OH- form) until pH 8-9. The resine was
partitioned between CH2C12 (2× 10 mL) and H20 (2× 10 mL), the organic phase then dried (Na2SO4)
and the solvent eliminated under vacuum affording pure (TLC) methylesters 9a (0.10 g, 39%): [~]D25
+5.6 (c 1.53, CH3COOH); IH NMR (DMSO-d6) 8 : 4 . 1 2 4 . 0 0 [m, 4H, P(OCH2CH3)2], 3.86 (s, 3H,
OCH3), 3.65 (dd, 1H, Jl=9, J2=3, CHCOOCH3), 3.41-3.19 (m, 3H), 2.73-2.51 (m, 4H), 2.30 (bs,
IH, NH), 2.15-1.85 (m, 4H), 1.52-1.37 Ira, 1H, CH(CH3)2], 1.16 [t, 6H, J=7, PO(CHeCH3)2], 0.89
[d, J=7, 3H, CH(CH3)e], 0.85 ppm [d, J=7, 3H, CH(CH3)2]; 13C NMR 6: 172.0, 64.9, 64.7, 63.5,
62.3, 56.0, 52.6, 50.4, 30.7, 23.6, 20.0, 19.3, 17.0, 16.3 ppm. Calculated for C16H33N2OsP: C, 52.70;
H, 9.13; N, 7.69. Found: C, 52.50; H, 9.21; N, 7.63.
(2R,5S)-2-Carbox3methyl-4-[3'-(diethoxyphosphinyl)propyl]-5-iso-bu~,l piperazine 9b
As previously described for 9a, from the crude acid 8b (0.59 g, 1.3 mmol) pure (TLC) methylesters
9b was recovered, (0.29 g, 61%); [0t]D25 +2.7 (c 1, CH3COOH), IH NMR (DMSO-d6) ~: 4.21-4.01
[m, 4H, P(OCH2CH3)2], 3.80 (s, 3H, OCH3), 3.55 (dd, IH, Jl=9, J2=3, CHCOOCH3), 3.32-3.13 (m,
3H), 2.83-2.59 (m, 4H), 2.42 (bs, 1H, NH), 2.20-1.90 (m, 4H), 1.64-1.43 [m, 3H, CH2CH(CH3)2],

Optically active CPP analogues
1639
1.04 [t, 6H, PO(CH2CH3)2], 0.83 [d, J=7, 3H, CH(CH3)2], 0.80 ppm [d, J=7, 3H, CH(CH3)2]; 13C
NMR (DMSO-d6) 8: 175.2, 66.2, 63.5, 61.9, 55.8, 55.5, 54.8, 54.0, 50.0, 45.9, 23.7, 22.3, 21.6, 20.0,
19.2 ppm. Calculated for CITH35N2OsP: C, 53.95; H, 9.32; N, 7.40. Found: C, 54.11; H, 9.23; N, 7.37.
Acknowledgements
We thank the Ministero dell'Universith e della Ricerca Scientifica e Tecnologica, Roma and the
CNR, Roma, for the financial support.
References
1. See for examples: Johnson, R.L.; Koerner, J.E, J. Med. Chem., 1988, 31, 2057-2066. Hashimoto,
K.; Shirahama, H., Tetrahedron Lett., 1991, 32. 2625-2628.
2. Hays, S.J.; Bigge, C.E; Novak, EM.; Drummond, J.T.; Bobovski, T.E; Rice, M.J.; Johnson, G.;
Brahce, L.J.; Coughenour, L.L., J. Med. Chem., 1990, 33, 2916-2924.
3. Falorni, M.; Porcheddu, A.; Giacomelli, G., Tetrahedron: Asymmetr3.~, 1996, 7, 1999-2005.
4. Carlsen, H.J.; Katsuki, T.; Martin, V.S.; Sharpless K.B.J. Org. Chem., 1981, 46, 3936.
5. The use of RuO2 instead ofRuCI3 as catalyst causes the oxidative decomposition of the substrates.
6. Shamma, M.; Deno, N.C.; Remar, J.F. Tetrahedron Lett., 1966, 1375.
7. Wilson, N.D.V.; Joule, J.A. Tetrahedron, 1968, 24, 5493-5497.
8. A sample of compound 1 could be recovered: IH NMR (D20): 8:4.12 (dd, J 1=9, J 2=3, 1H,
CHCOOH), 3.8--4.00 (m, 2H), 3.4-3.7 (m, 2H), 3.34 (t, 2H,CH2CHzCHzP), 2.34 (m, 1H), 2.02 (m,
2H, CHzCH2P), 1.68 (m, 2H, CHeP), 1.5-1.3 [m, IH, CH(CH3)2], 0.88 [d, J=7, 3H, CH(CH3)2],
0.83 ppm [d, J=7, 3H, CH(CH3)2].
9. Falorni, M.; Satta, M.; Conti, S.; Giacomelli, G. Tetrahedron: AsymmetO, 1993, 4, 2389-2398.
(Received in UK 19 March 1997)